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Biomedical subjects

C Chany

Publications and source records attributed to C Chany.

At least 19 recordsLinked to original sources
PubMed2002

Mandelic acid condensation polymer: novel candidate microbicide for prevention of human immunodeficiency virus and herpes simplex virus entry.

Presently marketed vaginal barrier methods are cytotoxic and damaging to the vaginal epithelium and natural vaginal flora when used frequently. Novel noncytotoxic agents are needed to protect men and women from sexually transmitted diseases. One novel candidate is a mandelic acid condensation polymer, designated SAMMA. The spectrum and mechanism of antiviral activity were explored using clinical isolates and laboratory-adapted strains of human immunodeficiency virus (HIV) and herpes simplex virus (HSV). SAMMA is highly effective against all CCR5 and CXCR4 isolates of HIV in primary human macrophages and peripheral blood mononuclear cells. SAMMA also inhibits infection of cervical epithelial cells by HSV. Moreover, it exhibits little or no cytotoxicity and has an excellent selectivity index. SAMMA, although not a sulfonated or sulfated polymer, blocks the binding of HIV and HSV to cells by targeting the envelope glycoproteins gp120 and gB-2, respectively, and also inhibits HSV entry postattachment. SAMMA is an excellent, structurally novel candidate microbicide that warrants further preclinical evaluation.

Antiviral Agents↗
PubMed2000

Role of sarcolectin (SCL) and interferons in coordinated T cell clonal expansion.

T cell multiplication is attributed to the growth factor interleukin-2 (IL-2), which is, however, only activated when a specific cell membrane-bound receptor can be expressed. We found in all human sera tested a lectin that we described and called sarcolectin (SCL). SCL is a molecularly cloned 55-kDa protein that stimulates DNA synthesis in all immunocompetent cells and inhibits the interferon (IFN)-dependent antiviral state. SCL is excreted in conditioned medium of T cell cultures grown under serum-free conditions, where it can be demonstrated regularly by Western blots. In such cultures, in addition to SCL and IL-2, IFN-gamma and IFN-alpha also can be found, likely as a feedback response to DNA stimulation. Considered together, the data suggest that coordinated clonal expansion of T cells is governed by SCL-IL-2, both which induce T cell proliferation and simultaneously activate IL-2 receptors. T cell replication is downregulated by the effect of feedback IFN-gamma and IFN-alpha. To initiate a new growth cycle, SCL is thought to block the residual IFN-dependent antiproliferative state.

Amino Acid Sequence↗
PubMed1999

Sarcolectin: complete purification for molecular cloning.

A great variety of vertebrate cells contain detectable amounts of lectins, able to stimulate the initiation of cellular DNA synthesis. One of them, sarcolectin (SCL) can block interferon (IFN) action, by inhibiting the synthesis and the expression of the IFN dependent secondary proteins. As a result, the IFN-induced antiviral state is abolished in the cells, which likely facilitates their replication. We identified a major 65 kDa and a minor 55 kDa protein, which could carry these cellular functions. Their purification, especially that of the 65 kDa, was difficult, because of the proximity of albumin. We devised therefore a two-step primary separation, followed by a four-step final purification, which are reported here. The purification was controlled by high pressure liquid chromatography (HPLC), SDS-PAGE electrophoresis and identified by Western blots. We found that only the minor 55 kDa protein can be considered as being sarcolectin, while the major 65 kDa band results from the binding of some SCL molecules to albumin. The major biological functions, namely, stimulation of DNA synthesis and cell agglutination were preserved to the end of the last purification step. This work is requisite for establishing the molecular structure of SCL by recombinant DNA technology.

Animals↗
PubMed1999

Sarcolectin (SCL): structure and expression of the recombinant molecule.

Interferons (IFNs) are major cytokines, responsible for down-regulating cell growth and for promoting cell differentiation. The sarcolectin (SCL) protein presented here blocks in the cells the established IFN-dependent interphase and stimulates DNA synthesis, probably in co-ordination with more specific growth factors or hormones. The SCL-DNA structure is closely related to that of cytokeratine K2C7 intermediate filaments, but the SCL is a monomer, or sometimes a dimer, which is excreted into the serum, where it is frequently bound to albumin. Its specific biological functions are carried by the beta sheets, and can be found on the two terminal domains of the molecule, the lectinic properties being located mainly on the N-terminus. The recombinant SCL molecule possesses the same biological functions as the native one, since it inhibits the IFN-dependent antiviral state both in human and in mouse cell cultures. On the contrary, antibodies raised against amino acids 41-55 located on the N-terminal domain of SCL inhibit this antagonistic effect. We postulate that the IFN and SCL proteins, because of their opposite biological functions, are in balance and are part of a feedback system operating the regulation of normal growth. In pathological cases, SCL could play a role in the development of tumors, as we have found in juvenile osteosarcomas or in AIDS cases.

Amino Acid Sequence↗
PubMed1998

GABA modulates cytotoxicity of immunocompetent cells expressing GABAA receptor subunits.

C57 black mouse splenic T lymphocytes effector cells were co-cultivated with Balb/c mouse splenic cells for sensitization; P815 DBA mouse mastocytoma target cells were then added and specific T cell-dependent cytotoxicity determined. This cytotoxicity increased after gamma-aminobutyric acid (GABA) treatment of the sensitized effectors, but decreased after GABA treatment of the targets. These GABA effects seemed to be specific since they were partially mimicked by linear but not ramified GABA analogues. Furthermore, they were likely mediated by GABAA receptor since GABAA receptor subunit mRNAs and protein could be demonstrated in effector or target immune specific cells, suggesting that under yet to be defined circumstances, GABA may affect T cell functions.

Animals↗
PubMed1997

Involvement of temperature sensitive syncytium inducing VSV or defective retroviruses in the development of spongiform encephalopathies.

Various enveloped viruses can induce syncytia in competent cells. Some temperature-sensitive mutants can express the trans-membrane viral G antigen under non-permissive conditions. The G antigen can then migrate at long distances, engulfing thousands of cells without producing any virus. When a temperature-sensitive vesicular stomatitis virus (VSV) infects a sensitive host, and under the condition that the G antigen is expressed, spongiosis can be induced in the central nervous system in the absence of detectable virus multiplication. We postulate that such a mechanism might be observed with various enveloped viruses, as recently illustrated with knock-out mice experimentally infected with defective murine leukemia virus (MULV).

Animals↗
PubMed1997

Localization and structure of v-mos in transformed mouse fibroblasts reverted by long-term interferon treatment to nonmalignancy.

We have reported previously that Moloney virus-transformed cells, when treated for over 200 passages in the presence of low concentrations of mouse interferon-alpha/beta, can be reverted to a stable nonmalignant status. The cells recover full contact inhibition and are unable to raise tumors when grafted in nude mice. In the present report, we show that whether reverted or malignant, these cells contain deleted v-mos oncogenes, which have lost 392 nucleotides. The truncated oncogenes contain a reduced and modified open reading frame but are able, however, to induce tumors when transfected in mouse 3T3 cells. As there is no difference either in the location or in the structure of this modified v-mos, whether yielded by reverted or malignant cells, we postulate that both cell lines derive from the same population and this modification does not play any role in the reversion process obtained through prolonged IFN-dependent selection. We suggest that reversion could be an epigenetic phenomenon, involving the constitutive synthesis of IFN-beta only in the reverted and not in the malignant cells. The continued persistence of such noncancerous cells could result at least partly from a balance involving the expression of v-mos, IFN-beta, and an IFN antagonist, sarcolectin. These reverted cells can undergo an unlimited number of passages, but they must be trypsinized before day 5 in confluent cultures. Thereafter, the cells stop dividing, cannot proliferate anymore, progressively show signs of apoptosis, and die.

Amino Acid Sequence↗
PubMed1993

[Mechanism of proliferation of cells transformed by the Moloney mouse sarcoma virus after stable reversion to a non-malignant state].

Prolonged interferon (IFN) treatment can convert Moloney sarcoma-transformed mouse Balb C fibroblasts to a stable non-malignant status. The cells recover a number of differentiated features, which are maintained even when IFN is permanently omitted from the tissue culture medium. We show here that reversion could be at least in part attributed to constitutive IFN beta synthesized only in the reverted cells. The continued replication of these cells, although unable to induce tumours in athymic mice, could be the result of the maintained expression of an IFN antagonist termed sarcolectin (SCL), a balance being struck between the effects of v-mos oncogene, interferon beta and SCLs. In agreement with Lampl et al. [11], we suggest that normal cell growth is discontinuous, consisting of sudden bursts followed by prolonged arrests which could be necessary to promote differentiation during the ensuing interphase.

Animals↗
PubMed1992

Enhancement by stable butyrate derivatives of antitumor and antiviral actions of interferon.

The use of n-butyric acid has been associated with induction of cell differentiation and bypassing of genetic defects in the suppression of malignancy. This biological response modifier satisfies the requirements for specificity and low toxicity, and its use can be considered as an alternative approach to conventional cancer chemotherapy. However, a lack of clinical efficacy has been observed with butyrate and attributed mainly to the rapid metabolism of the compound. Butyric acid pro-drugs derived from monosaccharides such as 3-O-butanoyl-1,2-O-isopropylidene-alpha-D-glucofuranose (MAG = 3but) have consequently been devised. Pharmacokinetic and biological advantages of MAG = 3but have been previously described. In the present report, we have studied the effect of MAG = 3but on murine interferon-alpha, beta (IFN) anticellular, antitumor and antiviral activities. In vitro, it appears that MAG = 3but predisposes malignant MSV cells to a later, complete establishment of the antiproliferative and the cell-differentiating effects of IFN, and the antiviral action of the latter in the same line of cells infected with encephalomyocarditis (EMC) virus. In vivo, combined treatment with MAG = 3but and IFN protects mice effectively against the fatal development of ascitic sarcoma 180 TG and the lethal effect of EMC virus infection.

Animals↗
PubMed1992

[Protective activity of monoacetone glucose 3-butyrate, prodrug of n-butyric acid, against the fatal effect of encephalomyocarditis virus in mice].

A comparative study was made, in the mouse, on antiviral properties of a prodrug of n-butyric acid derived from monosaccharides: monoacetone glucose 3-butyrate (MAG = 3but), and of a free form of n-butyric acid: arginine butyrate (BuO Arg). Preventive injection of MAG = 3but protected the mice twice as effectively as BuO Arg against the lethal effect of 100 LD50 of encephalomyocarditis virus. Under the same experimental conditions, monoacetone glucose (MAG) used as carrier of the biologically active moiety, was inactive on its own. Antiviral activity of MAG = 3but was shown not to be virucidal, but rather could involve stimulation of the immune system. This capability supplements known anticellular and antitumoral properties. In total these results indicate a prime therapeutic importance for this new molecule, pharmacokinetically suitable, with its very low toxicity, for clinical application. Combined use of MAG = 3but with biological response modifiers which have similar affinity, such as Interferon, is discussed.

Animals↗
PubMed1991

Butyric monosaccharide ester-induced cell differentiation and anti-tumor activity in mice. Importance of their prolonged biological effect for clinical applications in cancer therapy.

The interest of butyric salts is based on their capacity to promote differentiation of malignant cells and inhibition of tumor development. The phenotypic modifications are rapidly reversible and require the continuous presence of butyric salts in the target area, which raises problems for therapeutic applications. We show here that the covalent binding of n-butyric acid on natural polyhydroxylated compounds such as monosaccharides, especially 3- or 6-O-butanoyl-1,2-O-isopropylidene-alpha-D-glucofuranose, retains the majority of the biological properties of n-butyric acid. The delayed degradation of these covalent compounds is associated with an improved maintenance of cell differentiation and anti-tumor protection in mice. These butyric complexes thus seem potentially useful for therapeutic applications.

Animals↗
PubMed1991

Pharmacokinetics of butyric acid derivative with xylitol.

The short chain fatty acids, especially butyric acid salts have interesting biological properties. In some cases, transformed cells can recover a normal phenotype and in animal, butyrate salts increase antitumor resistance. Butyrate may be considered as possibly useful for antitumor therapy. But these products exhibit two essential disadvantages which restrict their clinical use in man: high concentrations required to achieve therapeutic effects and rapid excretion with short half life. In order to optimize the clinical use of butyrate, we studied a n-butyric acid ester obtained with xylitol selected for its physiological and metabolic inertia. Structure determination of tributyryl xylitol was carried out by mass and NMR spectrometry (MW = 344). The low toxicity and the antitumor effects of this ester, especially in association with Corynebacterium parvum and interferon, confirm its therapeutic interest. The slow excretion of this prodrug should make butyrate clinical use easier by preventing extensive systemic metabolism and metabolic side-effects due to cations of butyrate salts.

Animals↗
PubMed1990

Anti-tumor protection induced in mice by fatty acid conjugates: alkyl butyrates and poly(ethylene glycol) dibutyrates.

Simple fatty acids, especially butyrate salts, have interesting biological properties, since they are able to down-regulate cell growth and promote various differentiated cellular functions. Their use for anti-tumor treatment is, however, hampered by their over-rapid diffusion in the blood, followed by a short-lived biological action. We have therefore devised conjugates linking butyrate with either (i) aliphatic alcohols of increasing carbon numbers ranging from C4 to C12 or (ii) poly(ethylene glycols) of increasing molecular weights. In both cases, the resulting butyric esters can be hydrolysed by esterases which can release biologically active subunits from the synthetic compounds. As shown in the present study, only one conjugate in each series gave satisfactory anti-tumor protection: namely, I-octyl butyrate and poly(ethylene glycol 1000) dibutyrate respectively. A single immune-stimulatory injection of purified Corynebacterium parvum extract prior to administration of the conjugates significantly increased the anti-tumor potency.

Adjuvants, Immunologic↗
PubMed1990

Sarcolectin and interferon in the regulation of cell growth.

Sarcolectin is an endolectin present in a great variety of conjunctival tissues (muscles, cartilage, sarcomas), but also in brain or placental extracts of vertebrates, including primates. When purified to electrophoretical homogeneity as a 65-kd protein, it agglutinates cells and has an affinity for simple sugars. In addition, it is able to inhibit the synthesis of interferon (IFN)-dependent secondary proteins and to restore cells to their status ad primum. The biological effect of Poly(I).Poly(C)-induced feedback interferon is inhibited by the addition of sarcolectins, which also abolishes cellular refractoriness to repeated IFN induction. Similarly, sequential association of, first, Poly(I).Poly(C); 4-5 h later, sarcolectin restores the full capacity of both to promote cell growth, unrestrained by IFN. Indeed, the secondary proteins which are in the process of being synthesized are inhibited. In a great variety of animal cells, sarcolectin can also initiate growth after it has been blocked by IFN. This is not an all-or-none effect, but a balance may be struck by IFN and sarcolectin, depending on their respective concentrations and specific activity. We propose that the coordination of these cellular functions of Poly(I).Poly(C), IFN, and sarcolectin takes place in the form of a triangular growth-regulatory cycle and postulate that they thus maintain a balance during differentiated normal tissue development.

Animals↗